Breast cancer is a multi-factorial disease and depends on the genetic make up, the metabolomic profile of the individual as well as on the environment. A great diversity in the breast cancer incidence rate suggests both endogenous and exogenous factors contribute to the development and progression of the disease. The etiology of breast cancer is complex, but this hyperproliferative disorder is angiogenesis dependent, is a critical process in which the dynamic balance between pro-angiogenic and anti-angiogenic factors is shifted to the former by conditions created by the tumor and its microenvironment, including hypoxia, inflammation, and mutation in oncogenes or tumor suppressor genes, such as p53. Commonly known pro-angiogenic factors are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), placental growth factor (PIGF), and matrix metalloproteinases (MMPs). Endogenous anti-angiogenic factors include thrombospondin, angiostatin, tumstatin, and endostatin.
The prognosis of breast cancer depends upon the stage at which the tumor is diagnosed. The breast cancer statistics of 2010 estimated that the US will have 207,090 new cases of invasive and 54,010 new cases of non-invasive (in situ) breast cancer and about 39,840 will die from the disease. Although there are several therapeutic options, treatment is typically expensive and accompanied by a host of adverse side effects that are detrimental to patients' quality of life. In many cases, treatments are effective in only a small percentage of the total patient population so, multiple treatment options must be pursued sequentially until an effective option is found. The consequences of the suboptimal or in appropriate therapies include poor patient outcomes (both from side effects and lack of activity), as well as an economic burden on the healthcare system, the added costs of the physician's time, wasted drugs and increased hospitalization. Normal vasculature is quiescent in healthy adults with each endothelial cell dividing once every 10 years. In contrast, tissue remodeling and angiogenesis are crucial for the growth and metastasis of breast cancer, providing an attractive therapeutic target. Treatment strategies include either (a) targeting angiogenesis with endothelial toxins, growth factor antagonists, protease inhibitors, endogenous anti-angiogenics, anti-angiogenic chemotherapy, or (b) other targets.
Several lines of evidence now indicate that N-linked glycoproteins play an important role in capillary endothelial cell proliferation and differentiation. It has been suggested earlier that deoxymannojirimycin (an inhibitor of hybrid and complex-type N-glycans), inhibited the formation of capillary tubes when tested in vitro by plating capillary endothelial cells on fibronectin-coated dishes. In contrast, swainsonine (an inhibitor of complex-but not hybrid-type N-glycans), did not inhibit tube formation. Lectin affinity chromatography of 2-[3H] mannose-labeled glycopeptides from endothelial cells induced to form tubes did not reveal a striking difference in the spectrum of glycans compared to uninduced cells. However, the glycopeptides from swainsonine-treated cells were enriched in monosialylated hybrid-type glycans sensitive to alpha-fucosidase, beta-galactosidase, and beta-N-acetylhexosaminidase, suggestive of sialyl Lewis-X determinants.
Tunicamycin (a glucosamine-containing pyrimidine nucleoside and an antibiotic), a competitive inhibitor of N-acetylglucosaminyl 1-phosphate transferase has recently been shown to inhibit angiogenesis in vitro/in vivo as well as the breast tumor microvasculature and reduce the breast tumor growth in athymic nude mice. Tunicamycin was effective in double and triple negative breast tumors. The effect is mediated by ER stress followed by developing the unfolded protein response (upr) in tumor microvasculature and the induction of apoptosis.
Gold nanoparticles (NPs) and peptide-based nanostructures have been receiving significant attention over the past decade due to their potential applications in catalysis, chemical sensing, electronics, optics, sensors and biomedical applications. Particularly, monolayer-protected Au NPs using thiolated compounds to stabilize Au NPs have been gaining popularity for delivering various therapeutic agents such as drugs, proteins, and nucleic acids into their targets. Several types of Au NP conjugates have been prepared for potential drug delivery applications. For example, recent report indicated that polystyrene-functionalized Au NPs by the covalent attachment of thiol-terminated polystyrene has been prepared by anionic polymerization. Synthesis of Au NPs with tetra(ethylene glycol)ylated cationic ligands, fluorogenic ligands as well as polycaprolactone-methoxy poly(ethylene glycol) have also been carried out for the development of drug delivery systems. In a separate study, NP-polymer transfection vectors have recently been synthesized as well. While gold nanoparticles provide a versatile platform for the preparation of drug delivery devices, peptide based nanotubes self-assembled from peptide bolaamphiphiles (amino acid head groups covalently bound via hydrocarbon chain), exhibit several properties that make them promising biomaterial candidates, including facile self-assembly in aqueous solutions and adaptability to functionalization for increased biocompatibility. Further, the peptide head groups can be readily modified in order to manipulate and potentially alter the properties of the self-assembled micro and nanostructures. Although many applications related to peptide-based nanotubes have been investigated, the immense potential of peptide nanotubes as drug delivery devices is yet to be fully tapped.